Salivary glands are critical for oral health, and loss of normal function results in adverse secondary conditions in affected patients. Radiation therapy, used to treat head and neck cancers, as well as autoimmune diseases, cause irreversible damage to the salivary glands, specifically to the acinar cells primarily responsible for salivary secretion. Current therapies for salivary gland dysfunction are pallative and short term. Potential strategies for permanent restoration of gland function include cell replacement. Although evidence suggests that salivary glands have stem cells, they have not yet been isolated. Moreover, the extent of stem cell contribution to salivary gland maintenance is unclear, as it is also reported that, in adults, acinar cells are renewed by self-duplication. We have identified a salivary gland progenitor cell that is marked by expression of Ascl3. Lineage tracing shows that these progenitors generate duct cells and a subset of acinar cells, but not the majority of serous acinar cells in the submandibular and parotid glands. We propose that Ascl3-expressing cells, located in the ducts, are transient intermediate progenitor cells involved in salivary gland maintenance. As the majority of serous acinar cells in the submandibular and parotid glands are not derived from Ascl3- expressing cells, we hypothesize that serous acinar cells are specified by a separate distinct progenitor population. This proposal will establish the differentiation potential of salivary gland progenitor cells and investigate the ability of these cells to contribute to regeneration of an atrophic gland. We have three specific aims: (1) To examine the potential of Ascl3-expressing progenitor cells to contribute to the maintenance and regeneration of the salivary gland. (2) To determine the role of serious acinar progenitors in the salivary gland. (3) To test the ability of cultured progenitor cells to contribute to salivary gland regeneration following transplantation. The identification and characterization of progenitor cell types in the salivary gland is a critical step in the path to cell replacement therapies.